7z3p

Structural highlights

Disease

LEP_MOUSE Defects in Lep are the cause of profound obesity and type II diabetes.

Function

LEP_MOUSE Key player in the regulation of energy balance and body weight control. Once released into the circulation, has central and peripheral effects by binding LEPR, found in many tissues, which results in the activation of several major signaling pathways (PubMed:15899045, PubMed:16825198, PubMed:11373681, PubMed:12594516, PubMed:20620997). In the hypothalamus, acts as an appetite-regulating factor that induces a decrease in food intake and an increase in energy consumption by inducing anorexinogenic factors and suppressing orexigenic neuropeptides, also regulates bone mass and secretion of hypothalamo-pituitary-adrenal hormones. In the periphery, increases basal metabolism, influences reproductive function, regulates pancreatic beta-cell function and insulin secretion, is pro-angiogenic for endothelial cell and affects innate and adaptive immunity (By similarity) (PubMed:8589726, PubMed:10660043, PubMed:25383904, PubMed:25060689, PubMed:9732873, PubMed:12594516). In the arcuate nucleus of the hypothalamus, activates by depolarization POMC neurons inducing FOS and SOCS3 expression to release anorexigenic peptides and inhibits by hyperpolarization NPY neurons inducing SOCS3 with a consequent reduction on release of orexigenic peptides (By similarity) (PubMed:20620997, PubMed:11373681). In addition to its known satiety inducing effect, has a modulatory role in nutrient absorption. In the intestine, reduces glucose absorption by enterocytes by activating PKC and leading to a sequential activation of p38, PI3K and ERK signaling pathways which exerts an inhibitory effect on glucose absorption. Acts as a growth factor on certain tissues, through the activation of different signaling pathways increases expression of genes involved in cell cycle regulation such as CCND1, via JAK2-STAT3 pathway, or VEGFA, via MAPK1/3 and PI3K-AKT1 pathways (By similarity) (PubMed:16825198, PubMed:20620997). May also play an apoptotic role via JAK2-STAT3 pathway and up-regulation of BIRC5 expression (By similarity). Pro-angiogenic, has mitogenic activity on vascular endothelial cells and plays a role in matrix remodeling by regulating the expression of matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinases (TIMPs) (PubMed:16825198). In innate immunity, modulates the activity and function of neutrophils by increasing chemotaxis and the secretion of oxygen radicals. Increases phagocytosis by macrophages and enhances secretion of pro-inflammatory mediators. Increases cytotoxic ability of NK cells (Probable). Plays a pro-inflammatory role, in synergy with IL1B, by inducing NOS2 wich promotes the production of IL6, IL8 and Prostaglandin E2, through a signaling pathway that involves JAK2, PI3K, MAP2K1/MEK1 and MAPK14/p38 (PubMed:15899045). In adaptive immunity, promotes the switch of memory T-cells towards T helper-1 cell immune responses (By similarity). Increases CD4(+)CD25(-) T cells proliferation and reduces autophagy during TCR (T cell receptor) stimulation, through MTOR signaling pathway activation and BCL2 up-regulation (PubMed:25060689).[UniProtKB:P41159][UniProtKB:P50596]^{[1] [2] [3] [4] [5] [6] [7] [8] [9] [10] [11] [12]}

References

1. ↑ Ducy P, Amling M, Takeda S, Priemel M, Schilling AF, Beil FT, Shen J, Vinson C, Rueger JM, Karsenty G. Leptin inhibits bone formation through a hypothalamic relay: a central control of bone mass. Cell. 2000 Jan 21;100(2):197-207. PMID:10660043 doi:10.1016/s0092-8674(00)81558-5
2. ↑ Cowley MA, Smart JL, Rubinstein M, Cerdán MG, Diano S, Horvath TL, Cone RD, Low MJ. Leptin activates anorexigenic POMC neurons through a neural network in the arcuate nucleus. Nature. 2001 May 24;411(6836):480-4. PMID:11373681 doi:10.1038/35078085
3. ↑ Bates SH, Stearns WH, Dundon TA, Schubert M, Tso AW, Wang Y, Banks AS, Lavery HJ, Haq AK, Maratos-Flier E, Neel BG, Schwartz MW, Myers MG Jr. STAT3 signalling is required for leptin regulation of energy balance but not reproduction. Nature. 2003 Feb 20;421(6925):856-9. PMID:12594516 doi:10.1038/nature01388
4. ↑ Otero M, Lago R, Lago F, Reino JJ, Gualillo O. Signalling pathway involved in nitric oxide synthase type II activation in chondrocytes: synergistic effect of leptin with interleukin-1. Arthritis Res Ther. 2005;7(3):R581-91. PMID:15899045 doi:10.1186/ar1708
5. ↑ Gonzalez RR, Cherfils S, Escobar M, Yoo JH, Carino C, Styer AK, Sullivan BT, Sakamoto H, Olawaiye A, Serikawa T, Lynch MP, Rueda BR. Leptin signaling promotes the growth of mammary tumors and increases the expression of vascular endothelial growth factor (VEGF) and its receptor type two (VEGF-R2). J Biol Chem. 2006 Sep 8;281(36):26320-8. PMID:16825198 doi:10.1074/jbc.M601991200
6. ↑ Ramadori G, Fujikawa T, Fukuda M, Anderson J, Morgan DA, Mostoslavsky R, Stuart RC, Perello M, Vianna CR, Nillni EA, Rahmouni K, Coppari R. SIRT1 deacetylase in POMC neurons is required for homeostatic defenses against diet-induced obesity. Cell Metab. 2010 Jul 7;12(1):78-87. PMID:20620997 doi:10.1016/j.cmet.2010.05.010
7. ↑ Cassano S, Pucino V, La Rocca C, Procaccini C, De Rosa V, Marone G, Matarese G. Leptin modulates autophagy in human CD4+CD25 Metabolism. 2014 Oct;63(10):1272-9. PMID:25060689 doi:10.1016/j.metabol.2014.06.010
8. ↑ Flak JN, Patterson CM, Garfield AS, D'Agostino G, Goforth PB, Sutton AK, Malec PA, Wong JT, Germani M, Jones JC, Rajala M, Satin L, Rhodes CJ, Olson DP, Kennedy RT, Heisler LK, Myers MG Jr. Leptin-inhibited PBN neurons enhance responses to hypoglycemia in negative energy balance. Nat Neurosci. 2014 Dec;17(12):1744-1750. PMID:25383904 doi:10.1038/nn.3861
9. ↑ Chehab FF, Lim ME, Lu R. Correction of the sterility defect in homozygous obese female mice by treatment with the human recombinant leptin. Nat Genet. 1996 Mar;12(3):318-20. PMID:8589726 doi:10.1038/ng0396-318
10. ↑ Lord GM, Matarese G, Howard JK, Baker RJ, Bloom SR, Lechler RI. Leptin modulates the T-cell immune response and reverses starvation-induced immunosuppression. Nature. 1998 Aug 27;394(6696):897-901. PMID:9732873 doi:10.1038/29795
11. ↑ La Cava A, Matarese G. The weight of leptin in immunity. Nat Rev Immunol. 2004 May;4(5):371-9. PMID:15122202 doi:10.1038/nri1350
12. ↑ Allison MB, Myers MG Jr. 20 years of leptin: connecting leptin signaling to biological function. J Endocrinol. 2014 Oct;223(1):T25-35. PMID:25232147 doi:10.1530/JOE-14-0404